The primary aim of this project is to convert antiviral and antitumor nucleosides to the corresponding 5'-O-dibenzylphosphates (phosphotriester). Investigations into the mode of action of several antiviral or antitumor nucleosides indicate that the nucleoside triphosphates and not the nucleosides are the active agents. Furthermore, the administered nucleoside is successively phosphorylated to the triphosphate level by virus induced or cellular enzymes of a combination of both. It is thus reasoned that the 5'-monophosphate forms of the drug could be more advantageous than the corresponding nucleosides. the doubly charged nucleotides would, however, not be able to penetrate the cellular membrane. After purification and characterization these compounds will be submitted for antiviral and antitumor screening. Antiviral nucleosides, like 2',3'- dideoxycytidine (used in the treatment of AIDS), will be converted to their 5'-O-dibenzylphosphates derivatives via the corresponding 5'-phosphodi- chloridates. Variation in benzyl group (m- or p-substituted) can be achieved by treating the 5'-phosphochloridate with the appropriate alcohol or alkoxide ion. These phosphotriesters are electrically neutral, by virtue of phosphate dibenzylation, and should be more able to diffuse through the cellular membrane. Once inside the membrane the phosphodiester could undergo slow chemical hydrolysis to yield the corresponding phosphodiesters. The phosphodiesters can in turn be hydrolyzed enzymatically to either the 5'-mononucleotide or the nucleoside. Thus, hydrolysis studies will be conducted to determine the stability of these compounds in aqueous solution. Studies will also be conducted to determine whether the nature of the benzylic group has any effect on the rate of conversion of phosphotriesters to the corresponding phosphodiester. Timely phosphotriester hydrolysis could provide a continuous supply of the drug. If the hydrolysis rate is substituent dependent, then a further means of controlling the rate of drug release may also become available. Octanol- water partition coefficient values will be determined for all derivatives as a measure of their lipid solubility.